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II. Changes in Reproductive Hormones During the Aging Process

University of Washington and VA Puget Sound Health Care System (III) Seattle, Washington 98108

	Introduction

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IN BOTH males and females, normal aging is accompanied by changes in reproductive function. Unlike the female, in whom reproductive aging culminates in menopause and the cessation of ovarian function, reproductive aging in the male is a gradual process.

Many studies have assessed the changes in testosterone (T) and associated reproductive hormones that occur across the adult male life span. Serum T levels vary considerably depending on the overall health of the individual, smoking and alcohol use, obesity, and time of sampling. Although some earlier studies failed to show an age-related decline in serum T levels, it is now clear that there is a slow but continuous decline in average serum T after approximately age 20–30 yr (1, 2, 3). Whereas younger men have higher serum T levels in the mornings than in the evenings, this circadian rhythm is often lost in older men (4). Also of interest, serum levels of sex hormone-binding globulin (SHBG) increase with aging, while levels of free T and non-SHBG bound T decline, often to a greater extent that total T levels (3).

Although all women undergo menopause, it is unknown whether every man experiences a decline in circulating androgens with aging. It has been estimated that approximately 50% of healthy men between the ages of 50 and 70 yr have levels of bioavailable T that are below the lower limit of normal for men aged 20 to 40 yr (5). However, there are currently few longitudinal studies of T levels in healthy men over a substantial portion of their life span, and it is unknown what percentage of men actually experience a reduction in serum T (or bioavailable T) over time.

Assuming that T levels decrease in many men over time, on what basis should an older man be considered hypogonadal? If hypogonadism is defined strictly on the basis of serum T levels, a significant proportion of men over age 50 would meet the criteria for hypogonadism and could be considered candidates for T replacement. If the requirement of elevated gonadotropin levels is included, still a large number, perhaps 3–4% of all men in the 40–60 yr age group (6), would be classed as hypogonadal. Should certain symptoms of T deficiency be required to diagnose hypogonadism in a man with a "low" T level? As described elsewhere in this symposium, T deficiency has wide-ranging manifestations. Because of concomitant medical conditions and medications, though, it is often difficult to know whether a particular complaint is the result of primarily androgen deficiency or of other factors. Thus, the diagnosis of hypogonadism in the older man is not always straight-forward.

	References

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1. Gray A, Beline JA, McKinlay JB, Longcope C. 1991 An examination of research design effects on the association of testosterone and male aging: the results of a meta-analysis. J Clin Epidemiol. 44:671–684.[CrossRef][Medline]
2. Tenover, JS. 1994 Androgen administration to aging men. Endo Metab Clin N Amer. 23:877–892.
3. Tsitoura P, Bulat T. 1995 The aging male reproductive system. Endo Metab Clin N Amer. 24:295–315.
4. Bremner WJ, Vitiello MV, Prinz PN. 1983 Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 56:1278–1281.[Abstract]
5. Sih R, Morely JE, Kaiser FE, Perry HM, Patrick P, Ross C. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661–1667.[Abstract/Free Full Text]
6. Feldman HA, McKinlay JB, Longcope C. Hypogonadism: correlates in a large random sample of Massachusetts men. Proceedings of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997, p 1–317 (Abstract).

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